Heptane

Neurotoxicity

Description of key information

The weight of evidence indicates that Heptane is unlikely to present a hazard as a neurotoxicant.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: acute inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles

Principles of method if other than guideline:

Effect-air concentration regressions of Heptane was determined for 4 hour inhalation exposures in male rats and for 2 hour exposure in female mice. Inhibition of propagation and maintenance of the electrically evoked seizure discharge was used as a criterion of the acute neurotropic effect.

GLP compliance:

not specified

Limit test:

no

Species:

other: rats and mice

Strain:

other: (male albino SPF Wistar rats) and H-strain mice

Sex:

male/female

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

4 hour inhalation exposures in male rats
2 hour exposure in female mice

Frequency of treatment:

three or four exposures with intervals being at least 3 weeks

Remarks:

Doses / Concentrations:
Ranges of effective concentrations were estimated in preliminary experiments. Three concentrations were selected in the linear part of the effect-concentration curve, between 25 and 75 % of the maximum effect.
Basis:
no data

No. of animals per sex per dose:

4 rats
8 mice

Control animals:

yes, sham-exposed

Dose descriptor:

other: ECC (biological response amounting to 30 % of the maximum possible effect in rats)

Effect level:

ca. 12 000 mg/m³ air (nominal)

Sex:

male

Basis for effect level:

other: Width of a one-sided 90 % confidence interval (ppm): 730 Slope of the regression (%/ppm): 0.011

Remarks on result:

other:

Dose descriptor:

other: ECC (biological response amounting to 30 % of the maximum possible effect in mice)

Effect level:

ca. 21 000 mg/m³ air (nominal)

Sex:

female

Basis for effect level:

other: Width of a one-sided 90 % confidence interval (ppm): 1590 Slope of the regression (%/ppm): 0.007

Remarks on result:

other:

Dose descriptor:

other: Isoeffective concentration of heptane (ECC, mean of the value in rats and mice) expressed as percentage of the concentration of saturated vapors (CSV) at 37 °C

Effect level:

ca. 3.4 other: ECC/CSV (%)

Sex:

male/female

Remarks on result:

other:

Dose descriptor:

other: Isoeffective concentration of heptane (EC10, mean of the value in rats and mice) expressed as percentage of the concentration of saturated vapors (CSV) at 37 °C

Effect level:

ca. 0.9 other: EC10/CSV (%)

Sex:

male/female

Remarks on result:

other:

Conclusions:

Under the conditions of the test, Normal-Heptane was capable of blocking electrically evoked seizures at 2740 ppm (90% confidence interval = 730), underlining the effects on behaviour.

Executive summary:

Under the conditions of the test, Normal-Heptane was capable of blocking electrically evoked seizures at 2740 ppm (90% confidence interval = 730), underlining the effects on behaviour.

Endpoint conclusion

Quality of whole database:

1 supporting study available for assessement

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute neurotoxicity data is available for Heptane.

 

Heptane

Inhibition of propagation and maintenance of electrically evoked seizure discharge was tested as a parameter for the acute neurotropic effect of heptane in rodents (Frantik et al. 1994). Groups of 4 male rats and 8 female mice per dose were exposed by inhalation to ambient air or 3 concentrations selected in the linear part of an effect-concentration curve (between 25 and 75% of the maximum effect), which had been determined in preliminary experiments. Following exposure, measurements of biological effects were conducted. After a short electrical impulse applied through ear electrodes, the duration of tonic extension of hindlimbs (rats) and the velocity of tonic extension (mice) was measured. Data were processed by linear regression and the effect in the lower third of the dose-response curve (linear part) was chosen as the critical level. Isoeffective concentrations, corresponding to the critical level of effect (ECC), were interpolated and the 90% confidence intervals were calculated. The lowest effective concentration EC₁₀was determined as well. The interpolated estimates of concentrations evoking a 30% of the maximum possible effect were 2740 ppm (corresponding to ca. 12000 mg/m³) for rats and 4740 ppm (ca. 21000 mg/m³) for mice, with a width of a one-sided 90% confidence interval of 730 and 1590 ppm, respectively. The isoeffective concentration of Normal-Heptane (ECC and EC₁₀, mean of the value in rats and mice) expressed as percentage of the concentration of saturated vapours (CSV) at 37 °C were 3.4 and 0.9 %. Under the conditions of the test, Normal-Heptane was capable of blocking electrically evoked seizures, underlining the effects on behaviour.

 

Several other analogues have also been tested, namely octane; hydrocarbons, C6-C7, n-alkanes, isoalkanes, cyclics, < 5% n-hexane; hydrocarbons, C7-C9, isoalkanes; naphtha (petroleum), light alkylate (analogue substance for hydrocarbons, C7-C9, isoalkanes) and alkanes, C7-10-iso- (analogue substance for iso-octane). Studies on neurotoxic effects were performed in rodents upon single and/or repeated dose inhalation exposure to the test substances. In the majority of cases, measurement of various parameters of neurobehavioral response showed minimal to no adverse effects. In some cases, however, reversible neurobehavioural effects occurred at the higher dose levels. NOAEC values for neurobehavioural effects were ≥ 1000 ppm (ca. 3500-5200 mg/m³ depending on composition), mice being much more sensitive than rats (CEFIC, 2000, 2001; Lammers, 2001; Schreiner et al. 1998).

 

Therefore, Heptane is unlikely to present a hazard as a neurotoxicant.

 

References:

 

Balster, R. L. et al. (1997). Evaluation of the acute behavioral effects and abuse potential of a C8-C9 isoparaffin solvent. Drug and Alcohol Dependence 46: 125-135.

 

Bowen, S. E. and Balster, R. L. (1998). The Effects of Inhaled Isoparaffins on Locomotor Activity and Operant Performance in Mice. Pharmacology Biochemistry and Behavior, 61(3): 271-280.

 

CEFIC (2000). The Effects of Short-term Inhalatory Exposure to n-octane on Behaviour in the Rat. Unpublished. Testing laboratory: TNO Nutrition and Food Research Institute. Report no.: V99.429 Final. Owner company: CEFIC, Study number: 40.144/01.04. Report date: 2000-01-12.

 

CEFIC (2001). The Effects of Short-term Inhalatory Exposure to Iso-octane on Behaviour in the Rat. Unpublished. Testing laboratory: TNO Nutrition and Food Research Institute. Report no.: V99.430 Final.Owner company: CEFIC,. Study number: 40.144/01.09. Report date: 2001-02-15.

 

Lammers, J. H. C. M. (2001). The Effects of Short-term Inhalatory Exposure to Cypar 7 on Behaviour in the Rat. Unpublished. Testing laboratory: TNO Nutrition and Food Research Institute. Report no.: V99.1115 Final. Owner company: CEFIC, Study number: 40.144/01.10. Report date: 2001-02-15.

 

Schreiner, C. et al. (1998). Toxicity evaluation of petroleum blending streams: inhalation subchronic toxicity/neurotoxicity study of a light alkylate naphtha distillate in rats.Journal of Toxicology and Environmental Health (Part A) 55:277-296.

Justification for classification or non-classification

Based on available data, Heptane is unlikely to present a hazard as a neurotoxicant.